CN112358407A - Preparation method of flufenamic acid - Google Patents
Preparation method of flufenamic acid Download PDFInfo
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- CN112358407A CN112358407A CN202011283671.5A CN202011283671A CN112358407A CN 112358407 A CN112358407 A CN 112358407A CN 202011283671 A CN202011283671 A CN 202011283671A CN 112358407 A CN112358407 A CN 112358407A
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- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229960004369 flufenamic acid Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 168
- 239000000203 mixture Substances 0.000 claims abstract description 78
- 238000010438 heat treatment Methods 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 claims abstract description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 22
- 238000003756 stirring Methods 0.000 claims abstract description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000018044 dehydration Effects 0.000 claims abstract description 21
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000001256 steam distillation Methods 0.000 claims abstract description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims abstract description 13
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 13
- 229940045803 cuprous chloride Drugs 0.000 claims abstract description 13
- 238000010992 reflux Methods 0.000 claims abstract description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 11
- 235000017550 sodium carbonate Nutrition 0.000 claims abstract description 11
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000003825 pressing Methods 0.000 claims abstract description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 25
- 238000001816 cooling Methods 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 230000020477 pH reduction Effects 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 238000007599 discharging Methods 0.000 claims description 10
- 238000004321 preservation Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 7
- 238000007670 refining Methods 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 238000007664 blowing Methods 0.000 claims description 5
- 239000000498 cooling water Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000011085 pressure filtration Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 abstract description 11
- 238000006887 Ullmann reaction Methods 0.000 abstract description 6
- 239000002131 composite material Substances 0.000 abstract description 5
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940035676 analgesics Drugs 0.000 abstract description 3
- 239000000730 antalgic agent Substances 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 description 17
- 239000012452 mother liquor Substances 0.000 description 7
- 230000000007 visual effect Effects 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000521257 Hydrops Species 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- -1 chinese name Chemical compound 0.000 description 1
- OSVXSBDYLRYLIG-UHFFFAOYSA-N chlorine dioxide Inorganic materials O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Abstract
The invention discloses a preparation method of flufenamic acid, belonging to the technical field of production of anti-inflammatory and analgesic drugs. The method comprises the following steps: pressing DMF, o-chlorobenzoic acid and soda ash into a reaction tank, stirring to obtain a first mixture, heating the first mixture, pressing toluene, heating and dehydrating; stopping heating after dehydration is finished, adding m-amino benzotrifluoride, copper powder and cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating and dehydrating the second mixture; distilling toluene after dehydration; and (3) adding water for steam distillation after the toluene is distilled, and refluxing and distilling the m-amino trifluorotoluene after the steam distillation is finished. The invention adds the ligand auxiliary catalyst cuprous chloride on the basis of the initial catalyst copper powder to form a high-efficiency Ullmann reaction composite catalyst system, has the advantages of mild reaction conditions, compatibility to active functional groups and the like, improves the reaction yield, shortens the reaction time and reduces the energy consumption.
Description
Technical Field
The invention relates to the technical field of production of anti-inflammatory and analgesic drugs, and in particular relates to a preparation method of flufenamic acid.
Background
Flufenamic acid, also known as: flufenamic acid, a non-steroidal anti-inflammatory analgesic. The traditional Chinese medicine composition has the effects of relieving and reducing joint swelling, has obvious anti-inflammatory and analgesic effects, has better effects than aspirin, is similar to phenylbutazone and adrenocortical hormone, has antipyretic effects, has certain curative effects on eliminating swelling and hydrops of joints, has an action mechanism of inhibiting cyclooxygenase, reduces synthesis of prostatitis acid, achieves the purposes of resisting and relieving pain, belongs to peripheral analgesics, is only effective on light and moderate pain, and has the characteristics of no addiction, no sedation and hypnosis.
In the prior art, the preparation method of the flufenamic acid is a coupling reaction of diaryl and halogenated aromatic hydrocarbon under the traditional Ullmann reaction condition, and comprises the steps of completing a condensation reaction under the action of potassium carbonate in the presence of metallic copper or copper salt for 27 hours, then obtaining a crude product of the flufenamic acid through subsequent distillation and acidification, and refining to obtain the flufenamic acid.
Disclosure of Invention
In order to solve the problems of the prior art, the invention provides a preparation method of flufenamic acid, which comprises the following steps:
pressing DMF, o-chlorobenzoic acid and soda ash into a reaction tank, stirring to obtain a first mixture, heating the first mixture, pressing toluene, heating and dehydrating;
stopping heating after dehydration is finished, adding m-amino benzotrifluoride, copper powder and cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating and dehydrating the second mixture;
distilling toluene after dehydration; after toluene distillation, adding water for steam distillation, and after the steam distillation is finished, carrying out reflux distillation on the m-amino benzotrifluoride;
refluxing and distilling the m-amino benzotrifluoride, cooling, slowly adding hydrochloric acid for acidification, and heating and stirring after the acidification is finished to obtain a third mixture;
centrifuging the third mixture to obtain a crude product of flufenamic acid;
refining and decoloring the crude flufenamic acid to obtain a fourth mixture;
and crystallizing and drying the fourth mixture finished product to obtain the flufenamic acid.
Further, the mass ratio of DMF, o-chlorobenzoic acid, soda ash, toluene, m-amino benzotrifluoride, copper powder, cuprous chloride and water is 15-20: 40-55: 30-40: 40-80: 30-60: 0.02-0.08: 0.01-0.05: 20-50.
Further, heating the first mixture to 100-105 ℃.
Further, the toluene temperature rise dehydration time is 3-4 hours, and the temperature is 111-115 ℃.
Further, heating the second mixture to 105-120 ℃ for dehydration for 7 hours.
Further, distilling the distilled toluene at the temperature of 115-125 ℃ for 0.5-1 hour.
Further, after the m-amino benzotrifluoride is distilled, the temperature is reduced to 80-90 ℃, hydrochloric acid is slowly added, the pH value is adjusted to 4.0-5.0, and after acidification is finished, the mixture is heated to 90 ℃ and stirred for 30 minutes to obtain the third mixture.
Further, centrifuging the third mixture comprises: opening nitrogen protection, placing the third mixture at a low speed on a centrifugal machine, closing a discharge valve when the third mixture is full, carrying out high-speed filtration on the centrifugal machine for 5min, washing with hot water for 5min, and carrying out spin-drying for 5 min; then cooling with cold water; finally, washing with toluene twice, each time for 2min, 5min in the middle interval, and spin-drying for 10 min; stopping the machine and discharging to obtain the crude product of the flufenamic acid.
Further, the refining and decoloring of the crude flufenamic acid product comprises the following steps: adding methylbenzene, the crude flufenamic acid and medicinal carbon into a decoloring tank, starting steam heating to 90 ℃, and preserving heat for 1 hour, wherein the temperature is controlled to be 90-110 ℃ during heat preservation; and after heat preservation is finished, carrying out pressure filtration on the decolored feed liquid through a pressurizing filter, a sand core filter and a precision filter to obtain the fourth mixture.
Further, crystallizing and drying the fourth mixture finished product comprises: cooling the finished product crystallization tank to below 30 ℃ by adding cooling water, performing nitrogen replacement for 5-10 seconds after cooling, adding the fourth mixture, washing the materials with toluene for 2 times after each time of material addition, wherein each time is about 20 seconds, spin-drying for 5 minutes after washing is finished, and continuously performing nitrogen protection in the centrifugal process to obtain a wet product of the flufenamic acid;
and (3) drying the wet product of the flufenamic acid in a fluidized bed dryer, sampling and detecting the dry loss when the air outlet temperature of the fluidized bed dryer rises to 55-65 ℃, controlling the dry loss to be below 0.5%, stopping heating after the dry loss is detected to be qualified, cold-blowing to below 50 ℃, stirring, vibrating and discharging for 3 minutes to obtain the flufenamic acid.
The technical scheme provided by the embodiment of the invention has the following beneficial effects: the preparation method of flufenamic acid of the invention is to add the ligand auxiliary catalyst cuprous chloride on the basis of the initial catalyst copper powder to form a high-efficiency Ullmann reaction composite catalyst system, and has the advantages of mild reaction conditions, compatibility to active functional groups and the like, thereby not only improving the reaction yield, but also shortening the reaction time and reducing the energy consumption. And secondly, sodium carbonate (soda ash) is adopted to replace potassium carbonate, so that the cost is reduced, and the product quality is improved and guaranteed. In addition, the distillation process is optimized, the generation of waste water is reduced, and the pollutant discharge is greatly reduced.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
Fig. 1 is a flow chart of a preparation method of flufenamic acid according to an embodiment of the present invention.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
Example one
A method for preparing flufenamic acid, see fig. 1, comprising the steps of:
step (1): pressing DMF, o-chlorobenzoic acid and soda ash into a reaction tank, stirring to obtain a first mixture, heating the first mixture, pressing toluene, heating and dehydrating.
It is to be noted that DMF, chinese name, N-dimethylformamide, molecular formula: c3H7NO, molecular weight: 73.09, density: 0.9487. dimethylformamide is a chemical raw material with wide application and is an excellent solvent with wide application.
O-chlorobenzoic acid, white coarse powder, is easy to sublime. Insoluble in water, and soluble in organic solvent such as methanol, anhydrous ethanol, and diethyl ether. It is used for organic synthesis, bactericide and analytical reagent. The molecular formula is as follows: c7H5ClO2Molecular weight: 156.57.
step (2): and stopping heating after the dehydration is finished, adding m-amino benzotrifluoride, copper powder and cuprous chloride into the reaction tank, stirring to obtain a second mixture, and heating and dehydrating the second mixture.
And (3): distilling toluene after dehydration; and (3) adding water for steam distillation after the toluene distillation, and refluxing and distilling m-amino benzotrifluoride after the steam distillation is finished.
It should be noted that the standard for the end of the steam distillation: and (3) floating the m-amino trifluoro toluene layer in the visual cup of the water separator to 1/3 points of the visual cup within 10 minutes, and ending distillation until the acid is regulated.
And (4): and (3) refluxing and distilling m-amino benzotrifluoride, cooling, slowly adding hydrochloric acid for acidification, and heating and stirring after acidification to obtain a third mixture.
And (5): and centrifuging the third mixture to obtain a crude product of flufenamic acid.
And (6): refining and decoloring the crude flufenamic acid to obtain a fourth mixture.
And (7): and crystallizing and drying the fourth mixture finished product to obtain the flufenamic acid.
It should be noted that, the composite catalyst of copper powder and cuprous chloride is adopted, and in the second stage of condensation reaction, the reaction speed is slowed down, so that the reaction is continuously dehydrated under mild conditions, the phenomenon of flushing caused by violent reaction is prevented, the phenomenon of reaction tailing is effectively avoided, and the total reaction time is shortened.
Reacting with arylamine under the condition of a copper powder/cuprous chloride composite catalyst to generate the high-level arylamine in the Ullmann reaction of halogenated aromatic hydrocarbon. When the halogenated aromatic hydrocarbon has an electron-withdrawing group and the aromatic amine has an electron-donating group, the reaction is facilitated, and the compatibility of the active functional group is increased.
Example two
A method for preparing flufenamic acid, which is described in detail in the figure 1.
A step (101): 1.57L of DMF, 4kg of o-chlorobenzoic acid and 3kg of soda ash are pressed into a reaction tank and stirred to obtain a first mixture, the first mixture is heated to 100 ℃ and 4.6L of toluene is pressed into the reaction tank, the temperature is raised and the dehydration time is 3 hours, and the temperature is 111 ℃.
A step (102): and stopping heating after the dehydration is finished, adding 3kg of m-amino benzotrifluoride, 20g of copper powder and 10g of cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating the second mixture to 105 ℃ for dehydration for 7 hours.
Step (103): distilling toluene at 115 deg.C for 0.5 hr after dehydration; and (3) adding 2L of water for steam distillation after the toluene distillation, and refluxing and distilling m-amino benzotrifluoride after the steam distillation is finished.
A step (104): and (3) refluxing and distilling the m-amino benzotrifluoride, cooling to 80 ℃, slowly adding hydrochloric acid for acidification, adjusting the pH to 4.0, heating to 90 ℃ after acidification is finished, and stirring for 30 minutes to obtain a third mixture.
A step (105): opening nitrogen protection, placing a third mixture at a low speed on a centrifugal machine, closing a discharge valve when the third mixture is full, carrying out high-speed filtration on the centrifugal machine for 5min, washing with hot water for 5min, and carrying out spin-drying for 5 min; then cooling with cold water; finally, washing with toluene twice, each time for 2min, 5min in the middle interval, and spin-drying for 10 min; stopping the machine and discharging to obtain the crude product of the flufenamic acid.
Step (106): adding methylbenzene, a crude flufenamic acid product and medicinal carbon into a decoloring tank, starting steam heating to 90 ℃, and preserving heat for 1 hour, wherein the temperature is controlled at 90 ℃ during the heat preservation period; and (5) after heat preservation is finished, carrying out pressure filtration on the decolored feed liquid through a pressurizing filter, a sand core filter and a precision filter to obtain a fourth mixture.
Step (107): cooling the finished product crystallization tank to below 30 ℃ by adding cooling water, performing nitrogen replacement for 5 seconds after cooling, adding a fourth mixture, washing the materials for 2 times by using methylbenzene after each time of material addition, wherein each time is about 20 seconds, spin-drying for 5 minutes after washing is finished, and continuously performing nitrogen protection in the centrifugal process to obtain a wet product of the flufenamic acid;
and (3) putting the wet product of the flufenamic acid into a fluidized bed dryer for drying, sampling and detecting the dry loss when the outlet air temperature of the fluidized bed dryer rises to 55 ℃, controlling the dry loss to be below 0.5%, stopping heating after the dry loss is detected to be qualified, cold-blowing to below 50 ℃, stirring, vibrating and vibrating for 3 minutes, and discharging to obtain 5.96kg of the flufenamic acid.
EXAMPLE III
A method for preparing flufenamic acid, which is described in detail in the figure 1.
Step (201): 1.78L of DMF, 5kg of o-chlorobenzoic acid and 3.5kg of soda ash are pressed into a reaction tank and stirred to obtain a first mixture, the first mixture is heated to 103 ℃ and then 6.9L of toluene is pressed into the reaction tank, the temperature is raised and the dehydration time is 3.5 hours, and the temperature is 113 ℃.
Step (202): and stopping heating after the dehydration is finished, adding 4kg of m-amino benzotrifluoride, 50g of copper powder and 30g of cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating the second mixture to 113 ℃ for dehydration for 7 hours.
Step (203): distilling toluene at 120 deg.C for 0.7 hr after dehydration; and (3) adding 3L of water for steam distillation after the toluene distillation, and refluxing and distilling m-amino benzotrifluoride after the steam distillation is finished.
A step (204): and (3) refluxing and distilling m-amino benzotrifluoride, cooling to 85 ℃, slowly adding hydrochloric acid for acidification, adjusting the pH to 4.5, heating to 90 ℃ after acidification is finished, and stirring for 30 minutes to obtain a third mixture.
Step (205): opening nitrogen protection, placing a third mixture at a low speed on a centrifugal machine, closing a discharge valve when the third mixture is full, carrying out high-speed filtration on the centrifugal machine for 5min, washing with hot water for 5min, and carrying out spin-drying for 5 min; then cooling with cold water; finally, washing with toluene twice, each time for 2min, 5min in the middle interval, and spin-drying for 10 min; stopping the machine and discharging to obtain the crude product of the flufenamic acid.
Step (206): adding methylbenzene, a crude flufenamic acid product and medicinal carbon into a decoloring tank, starting steam heating to 90 ℃, and preserving heat for 1 hour, wherein the temperature is controlled at 100 ℃ during the heat preservation period; and (5) after heat preservation is finished, carrying out pressure filtration on the decolored feed liquid through a pressurizing filter, a sand core filter and a precision filter to obtain a fourth mixture.
Step (207): cooling the finished product crystallization tank to below 30 ℃ by adding cooling water, performing nitrogen replacement for 7 seconds after cooling, adding a fourth mixture, washing the materials for 2 times by using methylbenzene after each time of material addition, wherein each time is about 20 seconds, spin-drying for 5 minutes after washing is finished, and continuously performing nitrogen protection in the centrifugal process to obtain a wet product of the flufenamic acid;
and (3) putting the wet product of the flufenamic acid into a boiling dryer for drying, sampling and detecting the dry loss when the air outlet temperature of the boiling dryer rises to 60 ℃, controlling the dry loss to be below 0.5%, stopping heating after the dry loss is detected to be qualified, cold-blowing to below 50 ℃, stirring, vibrating and vibrating for 3 minutes, and discharging to obtain 7.78kg of the flufenamic acid.
Example four
A method for preparing flufenamic acid, which is described in detail in the figure 1.
Step (301): 2.1L of DMF, 5.5kg of o-chlorobenzoic acid and 4kg of soda ash are pressed into a reaction tank and stirred to obtain a first mixture, the first mixture is heated to 105 ℃, 9.2L of toluene is pressed into the mixture, and the mixture is heated and dehydrated for 4 hours at the temperature of 115 ℃.
Step (302): and stopping heating after the dehydration is finished, adding 6kg of m-amino benzotrifluoride, 80g of copper powder and 50g of cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating the second mixture to 120 ℃ for dehydration for 7 hours.
Step (303): distilling toluene at 125 deg.C for 1 hr after dehydration; and (3) after toluene distillation, adding 5L of water for steam distillation, and refluxing and distilling m-amino benzotrifluoride after the steam distillation is finished.
Step (304): and (3) refluxing and distilling m-amino benzotrifluoride, cooling to 90 ℃, slowly adding hydrochloric acid for acidification, adjusting the pH to 5, heating to 90 ℃ after acidification is finished, and stirring for 30 minutes to obtain a third mixture.
Step (305): opening nitrogen protection, placing a third mixture at a low speed on a centrifugal machine, closing a discharge valve when the third mixture is full, carrying out high-speed filtration on the centrifugal machine for 5min, washing with hot water for 5min, and carrying out spin-drying for 5 min; then cooling with cold water; finally, washing with toluene twice, each time for 2min, 5min in the middle interval, and spin-drying for 10 min; stopping the machine and discharging to obtain the crude product of the flufenamic acid.
Step (306): adding methylbenzene, a crude flufenamic acid product and medicinal carbon into a decoloring tank, starting steam heating to 90 ℃, and preserving heat for 1 hour, wherein the temperature is controlled at 110 ℃ during the heat preservation period; and (5) after heat preservation is finished, carrying out pressure filtration on the decolored feed liquid through a pressurizing filter, a sand core filter and a precision filter to obtain a fourth mixture.
Step (307): cooling the finished product crystallization tank to below 30 ℃ by adding cooling water, performing nitrogen replacement for 10 seconds after cooling, adding a fourth mixture, washing the materials for 2 times by using methylbenzene after each time of material addition, wherein each time is about 20 seconds, spin-drying for 5 minutes after washing is finished, and continuously performing nitrogen protection in the centrifugal process to obtain a wet product of the flufenamic acid;
and (3) putting the wet product of the flufenamic acid into a boiling dryer for drying, sampling and detecting the dry loss when the air outlet temperature of the boiling dryer rises to 65 ℃, controlling the dry loss to be below 0.5%, stopping heating after the dry loss is detected to be qualified, cold-blowing to below 50 ℃, stirring, vibrating and vibrating for 3 minutes, and discharging to obtain 8.75kg of the flufenamic acid.
It should be noted that, in order to save resources, mother liquor recovery is required after the flufenamic acid preparation is completed. And (3) recovering a finished product mother solution: transferring the finished mother liquor into a finished mother liquor recovery tank, and heating the tank to about 100 ℃. Adding water when the temperature rises to about 105 ℃. And (5) when the recovery is finished, whether the recovery is complete is identified, and the recovery is finished by observing that a visual cup of the condenser does not contain methylbenzene. In the recovery process, the pressure in the recovery tank is normal, and the temperature of the recovery tank is not higher than 115 ℃. And after recovery, closing steam and related valves, separating water (water at the lower layer) in the toluene receiving tank to the water applying tank, sampling the separated toluene, performing quality inspection, pumping the qualified toluene to a toluene storage tank, and recording the quantity of the toluene. The toluene in the toluene storage tank is directly used for production. The recovery of 4 consecutive batches is finished. Pressing a batch of finished mother liquor to a recovery tank, pressing the mother liquor to a crystallizing tank, cooling, and centrifuging when the temperature is reduced to 25 ℃. The amount of crude recovered was recorded. Recovering the crude product and feeding the crude product to refining and decoloring.
And (3) recovering a crude mother solution: transferring the crude mother liquor into a recovery tank, heating and recovering. During the recovery process, water is added, and the temperature of the tank is controlled to be about 100 ℃. Adding water for the first time when the temperature rises to about 105 ℃, paying attention to identify whether the recovery is complete or not when the recovery is finished, observing whether methylbenzene exists in a visual cup of the condenser, and if methylbenzene exists in the visual cup, supplementing water for the second time and continuing recovering until the methylbenzene is completely recovered. In the process of recovering the crude product mother liquor toluene, the pressure in a recovery tank is normal, and the temperature of the tank is not higher than 115 ℃. And after recovery, closing steam and related valves, distributing water (water at the lower layer) in the toluene receiving tank to the water recycling tank, sampling the distributed toluene, conveying to quality inspection detection, pumping to a toluene storage tank by a pump after the detection result is qualified, recording the amount of the toluene, and filling a material circulation card in time. The toluene in the toluene storage tank is directly used for production.
It should also be noted that in the existing synthetic process of the mefenamic acid, under the traditional Ullmann reaction condition, the coupling reaction of diaryl and halogenated aromatic hydrocarbon needs to be carried out at a temperature of 200 ℃ or higher, the reaction tailing phenomenon is obvious, the problem of incomplete reaction exists, about 20 hours is needed, the yield is about 70%, the reaction temperature is high, the time is long, the heat energy loss is large, the risk in operation is high, the number of byproducts is large, the product color is poor, the yield is low, and the byproduct treatment cost is high.
In the preparation method of flufenamic acid, a ligand auxiliary catalyst is added on the basis of an initial catalyst to form a high-efficiency Ullmann reaction composite catalyst system, so that the reaction is carried out under mild conditions, the reaction does not generate tailing, the reaction end point is clear, the reaction is finished within about 12 hours, the yield is about 88%, the reaction conditions are mild, the time is short, the operability is strong, byproducts are reduced, the product quality is improved, the environmental protection is greatly saved, and the product yield is obviously improved.
The above-mentioned serial numbers of the embodiments of the present invention are merely for description and do not represent the merits of the embodiments.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A method for preparing flufenamic acid, comprising:
pressing DMF, o-chlorobenzoic acid and soda ash into a reaction tank, stirring to obtain a first mixture, heating the first mixture, pressing toluene, heating and dehydrating;
stopping heating after dehydration is finished, adding m-amino benzotrifluoride, copper powder and cuprous chloride into a reaction tank, stirring to obtain a second mixture, and heating and dehydrating the second mixture;
distilling toluene after dehydration; after toluene distillation, adding water for steam distillation, and after the steam distillation is finished, carrying out reflux distillation on the m-amino benzotrifluoride;
refluxing and distilling the m-amino benzotrifluoride, cooling, slowly adding hydrochloric acid for acidification, and heating and stirring after the acidification is finished to obtain a third mixture;
centrifuging the third mixture to obtain a crude product of flufenamic acid;
refining and decoloring the crude flufenamic acid to obtain a fourth mixture;
and crystallizing and drying the fourth mixture finished product to obtain the flufenamic acid.
2. The preparation method of flufenamic acid according to claim 1, wherein the mass ratio of DMF, o-chlorobenzoic acid, soda ash, toluene, m-amino benzotrifluoride, copper powder, cuprous chloride and water is 15-20: 40-55: 30-40: 40-80: 30-60: 0.02-0.08: 0.01-0.05: 20-50.
3. The method according to claim 2, wherein the first mixture is heated to 100 to 105 ℃.
4. The method for preparing flufenamic acid according to claim 3, wherein the toluene is dehydrated at 111-115 ℃ for 3-4 hours at a temperature.
5. The method of claim 4, wherein the second mixture is heated to 105-120 ℃ and dehydrated for 7 hours.
6. The method of claim 5, wherein the distilled toluene is distilled at 115-125 ℃ for 0.5-1 hour.
7. The method for preparing flufenamic acid according to claim 6, wherein the m-amino benzotrifluoride is distilled, then cooled to 80-90 ℃, hydrochloric acid is slowly added to adjust the pH to 4.0-5.0, and after acidification is finished, the mixture is heated to 90 ℃ and stirred for 30 minutes to obtain the third mixture.
8. The method of claim 7, wherein centrifuging the third mixture comprises: opening nitrogen protection, placing the third mixture at a low speed on a centrifugal machine, closing a discharge valve when the third mixture is full, carrying out high-speed filtration on the centrifugal machine for 5min, washing with hot water for 5min, and carrying out spin-drying for 5 min; then cooling with cold water; finally, washing with toluene twice, each time for 2min, 5min in the middle interval, and spin-drying for 10 min; stopping the machine and discharging to obtain the crude product of the flufenamic acid.
9. The method for preparing flufenamic acid according to claim 8, wherein the refining and decoloring of the crude flufenamic acid comprises: adding methylbenzene, the crude flufenamic acid and medicinal carbon into a decoloring tank, starting steam heating to 90 ℃, and preserving heat for 1 hour, wherein the temperature is controlled to be 90-110 ℃ during heat preservation; and after heat preservation is finished, carrying out pressure filtration on the decolored feed liquid through a pressurizing filter, a sand core filter and a precision filter to obtain the fourth mixture.
10. The method of claim 9, wherein crystallizing and drying the fourth mixture comprises: cooling the finished product crystallization tank to below 30 ℃ by adding cooling water, performing nitrogen replacement for 5-10 seconds after cooling, adding the fourth mixture, washing the materials with toluene for 2 times after each time of material addition, wherein each time is about 20 seconds, spin-drying for 5 minutes after washing is finished, and continuously performing nitrogen protection in the centrifugal process to obtain a wet product of the flufenamic acid;
and (3) drying the wet product of the flufenamic acid in a fluidized bed dryer, sampling and detecting the dry loss when the air outlet temperature of the fluidized bed dryer rises to 55-65 ℃, controlling the dry loss to be below 0.5%, stopping heating after the dry loss is detected to be qualified, cold-blowing to below 50 ℃, stirring, vibrating and discharging for 3 minutes to obtain the flufenamic acid.
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| CN114426498A (en) * | 2022-02-15 | 2022-05-03 | 营口兴福化工有限公司 | Flufenamic acid synthesis method |
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